RESUMEN

BACKGROUND: Laparoscopic surgery develops rapidly in both elective and emergency settings. The study aimed to determine the role of different laparoscopic methods for the emergency treatment of complicated diverticulitis. METHODS: MEDLINE, EMBASE, Science Citation Index Expanded, and the Cochrane database were searched up to November 2019 to identify all published articles related to the topic. Statistical analysis was performed using Stata 15. RESULTS: Fourteen publications were included in the analysis. Laparoscopic surgery was applied in 425 patients, and 493 patients underwent open colon resection (OCR). Postoperative mortality, morbidity, severe complications, and reoperation rates were not significantly different between the laparoscopic and open surgery groups. Subgroup analysis was performed based on the different laparoscopic methods (laparoscopic colon resection [LCR] and laparoscopic lavage and drainage [LLD]). Subgroup analysis indicated that LCR was superior to OCR in terms of morbidity, while OCR was superior to LLD in terms of severe complications. CONCLUSIONS: The safety of laparoscopic surgery for the emergency treatment of complicated diverticulitis is related to different surgical methods. LCR is suggested to be a better choice according to the postoperative outcomes. More definite conclusions can be drawn in future randomized controlled trials.

Asunto(s)

Diverticulitis del Colon/cirugía , Laparoscopía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Laparoscopía/efectos adversos , Laparoscopía/mortalidad , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología

RESUMEN

BACKGROUND: Overexpression of SQSTM1 (sequestosome 1, P62) and nuclear factor-κB (NF-κB) plays an important role in the invasion and metastasis of a variety of malignant tumors. AIM: To explore the expression of P62 and NF-κB in pancreatic cancer and their relationship with clinicopathological features. METHODS: The expression levels of P62 and NF-κB were analyzed by immunohistochemistry with a tissue chip containing 40 cases of human pancreatic carcinoma. Then we analyzed the correlation among P62 expression, phospho-P65 expression, and clinicopathological features of pancreatic carcinoma samples. RESULTS: P62 expression was mainly observed in the cytoplasm of pancreatic carcinoma cells. Phosphorylated P65 (phospho-P65) was mainly expressed in the nucleus and cytoplasm of pancreatic carcinoma cells. There was a significant difference in P62 expression among T stages. And a significant difference in phosphor-P65 expression among pathology types was noted. In the cases with strongly positive P62 expression, significant differences were found in age. And there were significant differences in T stage and tumor-node-metastasis stage in the cases with strongly positive phosphor-P65 expression. CONCLUSION: In pancreatic carcinoma, P62 expression is significantly correlated with T stage. It may be a valuable malignant indicator for human pancreatic carcinoma.

RESUMEN

BACKGROUND: Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-κB) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway. AIM: To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells. METHODS: Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth. RESULTS: IL-1 receptor antagonist could decrease the expression of IL-1α and IL-1ß and downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line. CONCLUSION: Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.

RESUMEN

Overcoming oxidative stress is a critical step for tumor growth and metastasis, however the underlying mechanisms in gastric cancer remain unclear. In this study, we found that overexpression of nicotinamide nucleotide transhydrogenase (NNT) was associated with shorter overall and disease free survival in gastric cancer. The NNT is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Knockdown of NNT caused significantly NADPH reduction, induced high levels of ROS and significant cell apoptosis under oxidative stress conditions such as glucose deprival and anoikis. In vivo experiments showed that NNT promoted tumor growth, lung metastasis and peritoneal dissemination of gastric cancer. Moreover, intratumoral injection of NNT siRNA significantly suppressed gastric tumor growth in patient-derived xenograft (PDX) models. Overall, our study highlights the crucial functional roles of NNT in redox regulation and tumor progression and thus raises an important therapeutic hypothesis in gastric cancer.

Asunto(s)

NADP Transhidrogenasas/metabolismo , NADP/metabolismo , Estrés Oxidativo , Neoplasias Gástricas/patología , Animales , Apoptosis , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Homeostasis , Humanos , Ratones Desnudos , NADP Transhidrogenasas/análisis , NADP Transhidrogenasas/genética , Oxidación-Reducción , Pronóstico , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo

RESUMEN

BACKGROUND: The use of glue to fix mesh instead of sutures in Lichtenstein inguinal hernia repair has been accepted worldwide, with the increasing worries about postoperative chronic groin pain and recurrence. The aim of this meta-analysis was to clarify which mesh fixation method was more suitable in Lichtenstein inguinal hernia repair. METHODS: Articles published up to July 2017 were searched using MEDLINE, the Cochrane Library, Embase, and the Web of Science. Randomized controlled trials (RCTs) comparing glue versus suture mesh fixation in Lichtenstein inguinal hernia repair were included in the review. The quality assessment and data extraction of included studies were applied by 2 independent authors. Statistical analysis was performed using RevMan 5.2 software. RESULTS: Thirteen RCTs with 2375 patients were eligible for inclusion. Eight trials compared synthetic glue with suture fixation and 5 compared biological glue with suture fixation. The results showed that there was a lower incidence of early chronic pain (subgroup analysis, biological glue versus sutures, odds ratio (OR) = 0.41; 95% confidence interval (CI), 0.19-0.90; P = .03), and hematoma (subgroup analysis, synthetic glue versus sutures, OR = 0.56; 95% CI, 0.34-0.95; P = .03) in the glue fixation group. Suture mesh fixation method cost more time in operation than glue (mean difference = -4.60, 95% CI -7.60 to -1.60; P = .003). There was no evidence of an increase in chronic pain or recurrence rates with glue fixation method in the long-term follow-up. CONCLUSIONS: Mesh fixation with glue compared with sutures in Lichtenstein repair inguinal hernia is faster and less painful, without an increasing in terms of recurrence rates in the long term.

Asunto(s)

Adhesivos/efectos adversos , Hernia Inguinal/cirugía , Herniorrafia/instrumentación , Mallas Quirúrgicas , Técnicas de Sutura/efectos adversos , Adhesivos/administración & dosificación , Adulto , Femenino , Herniorrafia/métodos , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Dolor Postoperatorio/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Suturas , Resultado del Tratamiento

RESUMEN

AIM: To investigate the effect of ischaemia and reperfusion (I/R) injury on the Ca2+-ATPase activation in the intestinal tissue of a rat autologous orthotopic liver transplantation model and to determine if hypoxia preconditioning (HP) therapy induces HIF-1α to protect rat intestinal tissue against I/R injury. METHODS: Rats received non-lethal hypoxic preconditioning therapy to induce HIF-1α expression. We used an autologous orthotopic liver transplantation model to imitate the I/R injury in intestinal tissue. Then, we detected the microstructure changes in small intestinal tissues, Ca2+-ATPase activity, apoptosis, and inflammation within 48 h postoperatively. RESULTS: HIF-1α expression was significantly increased in intestinal tissue at 12 h postoperatively in rats that were exposed to a hypoxic environment for 90 min compared with a non-HP group (HP vs AT, P = 0.0177). Pathological analysis was performed on the intestinal mucosa cells, and the cells in the HP group appeared healthier than the cells in the AT group. The Ca2+-ATPase activity in the small intestinal cells in the AT group was significantly lower after the operation, and the Ca2+-ATPase activity in the HP group recovered faster than that in the AT group at 6 h postoperatively (HP vs AT, P = 0.0106). BCL-2 expression in the HP group was significantly higher than that in the AT group at 12 h postoperatively (HP vs AT P = 0.0010). The expression of the inflammatory factors NO, SOD, IL-6, and TNF-α was significantly lower in the HP group than in the AT group. CONCLUSION: Hypoxia-induced HIF-1α could protect intestinal mucosal cells against mitochondrial damage after I/R injury. HP could improve hypoxia tolerance in small intestinal mucosal cells and increase Ca2+-ATPase activity to reduce the apoptosis of and pathological damage to intestinal cells. HP could be a useful way to promote the earlier recovery of intestinal function after graft procedure.

Asunto(s)

ATPasas Transportadoras de Calcio/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Precondicionamiento Isquémico/métodos , Trasplante de Hígado/efectos adversos , Daño por Reperfusión/prevención & control , Animales , Apoptosis , Hipoxia de la Célula/fisiología , Modelos Animales de Enfermedad , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Masculino , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

NF-κB essential modulator (NEMO) binds and regulates IκB kinase (IKK) and is required for NF-κB activation. The NEMO-binding domain peptide (NBDP) of IKK was found to inhibit NF-κB activation and promote apoptosis in cancer cells. Studies have shown that constitutive NF-κB activation, one of the signature molecular alterations in pancreatic ductal adenocarcinoma (PDAC), is a potential therapeutic target. However, preclinical and therapeutic evidence that supports direct targeting of IKK activation in therapy is lacking. The aim of this study was to determine whether the combination of NBDP and gemcitabine would sensitize pancreatic cancer to the gemcitabine. We confirmed that NBDP inhibited NF-κB activation and found that NBDP indeed promoted chemo-sensitivity to gemcitabine in PDAC. NBDP increased PARP and caspase 3 cleavage in the apoptosis pathway, increased apoptosis of PDAC cells, and suppressed PDAC cell growth in vitro. In addition, NBDP combined with gemcitabine significantly decreased levels of NF-κB activity and inhibited the growth of PDAC in vivo in an orthotopic xenograft mouse model. Mechanistic investigations showed that NBDP effectively competed with NEMO/IKKγ for binding to IKKs and thus inhibited IKK and NF-κB activation, down-regulated expression levels of Erk, and decreased PDAC cell growth. Taken together, our current data demonstrate that NBDP sensitizes human pancreatic cancer to gemcitabine by inhibiting the NF-κB pathway. NBDP is a potential adjuvant chemotherapeutic agent for treating pancreatic cancer.

Asunto(s)

Carcinoma Ductal Pancreático/tratamiento farmacológico , Quinasa I-kappa B/farmacología , FN-kappa B/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Quinasa I-kappa B/administración & dosificación , Quinasa I-kappa B/metabolismo , Ratones , Ratones Desnudos , FN-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fragmentos de Péptidos/administración & dosificación , Péptidos/administración & dosificación , Péptidos/farmacología , Dominios Proteicos , Distribución Aleatoria , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina

RESUMEN

Kras activation and p16 inactivation are required to develop pancreatic ductal adenocarcinoma (PDAC). However, the biochemical mechanisms underlying these double alterations remain unclear. Here we discover that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyse the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 requires catalytic subunit p22phox, which is upregulated following Kras activation. Both alterations are also detectable in PDAC cell lines and patient specimens. Furthermore, we show that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC cell growth. Mechanistically, NOX4 was induced through p16-Rb-regulated E2F and p22phox was induced by KrasG12V-activated NF-κB. In conclusion, we provide a biochemical explanation for the cooperation between p16 inactivation and Kras activation in PDAC development and suggest that NOX4 is a potential therapeutic target for PDAC.

Asunto(s)

Carcinoma Ductal Pancreático/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , NADPH Oxidasa 4/metabolismo , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Pruebas de Enzimas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , NADP/metabolismo , NADPH Oxidasas/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Oxidación-Reducción , Páncreas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment.

Asunto(s)

Acrilamidas/farmacología , Antimetabolitos Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , NAD/metabolismo , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Piperidinas/farmacología , Regiones no Traducidas 3' , Animales , Sitios de Unión , Carcinoma Ductal Pancreático/enzimología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Desoxicitidina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Glucólisis/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , MicroARNs/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Nicotinamida Fosforribosiltransferasa/metabolismo , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Interferencia de ARN , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina

RESUMEN

OBJECTIVE: Aim of this study is to protect donor liver against ischemia-reperfusion injury by abating Cytochrome C induced apoptosome on rat model. METHODS: A total of 25 clean SD inbred male rats were used in this research. The rats in ischemia-reperfusion injury group (I/R group, n=5) were under liver transplantation operation; rats in dichloroacetate diisopropylamine group (DADA group, n=5) were treated DADA before liver transplantation; control group (Ctrl group, n=5); other 10 rats were used to offer donor livers. RESULTS: In DADA therapy group, Cytochrome C expression in donor hepatocellular cytoplasm was detected lower than that in I/R group. And the Cytochrome C induced apoptosome was also decreased in according to the lower expressions of Apaf-1 and Caspase3. Low level of cleaved PARP expression revealed less apoptosis in liver tissue. The morphology of donor liver mitochondria in DADA group was observed to be slightly edema but less than I/R group after operation 12 h. The liver function indexes of ALT and AST in serum were tested, and the results in DADA group showed it is significantly lower than I/R group after operation 12 h. The inflammation indexes of IL-6 and TNF-α expressions in DADA group were significantly lower than that in I/R group after operation 24 h. CONCLUSION: The dichloroacetate diisopropylamine treatment could protect the hepatocellular mitochondria in case of the spillage of Cytochrome C induced apoptosome, and protect the liver against ischemia-reperfusion injury. Thus, it may be a method to promote the recovery of donor liver function after transplantation.

RESUMEN

AIM: To investigate the expression of integrin αvß6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients. METHODS: Immunohistochemistry was used to determine the expressions of integrin αvß6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ(2) test and Fisher's exact test. Expression correlation of αvß6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvß6 and MMP-9 levels (that is, both markers positive, both markers negative, αvß6 positive with MMP-9 negative, and αvß6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis. RESULTS: The expressions of integrin αvß6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvß6 expression, and 42.06% for MMP-9 expression. The expression of αvß6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvß6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvß6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvß6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvß6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvß6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvß6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007). CONCLUSION: The expression of αvß6 and MMP-9 are closely correlated, and the combinational pattern of αvß6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.

Asunto(s)

Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Integrinas/análisis , Metaloproteinasa 9 de la Matriz/análisis , Neoplasias Gástricas/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Riesgo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

Pancreatic cancer is an aggressive disease with dismal prognosis. It is of paramount importance to understand the underlying etiological mechanisms and identify novel, consistent, and easy-to-apply prognostic factors for precision therapy. TUSC3 (tumor suppressor candidate 3) was identified as a potential tumor suppressor gene and previous study showed TUSC3 is decreased in pancreatic cancer at mRNA level, but its putative tumor suppressor function remains to be verified. In this study, TUSC3 expression was found to be suppressed both at mRNA and protein levels in cell line models as well as in clinical samples; decreased TUSC3 expression was associated with higher pathological TNM staging and poorer outcome. In three pairs of cell lines with different NF-κB activity, TUSC3 expression was found to be reversely correlated with NF-κB activity. TUSC3-silenced pancreatic cancer cell line exhibited enhanced potential of proliferation, migration and invasion. In an orthotopic implanted mice model, TUSC3 silenced cells exhibited more aggressive phenotype with more liver metastasis. In conclusion, the current study shows that decreased immunological TUSC3 staining is a factor prognostic of poor survival in pancreatic cancer patients and decreased TUSC3 promotes pancreatic cancer cell proliferation, invasion and metastasis. The reverse correlation between NF-κB activity and TUSC3 expression may suggest a novel regulation pattern for this molecule.

Asunto(s)

Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Análisis Multivariante , FN-kappa B/metabolismo , Invasividad Neoplásica , Trasplante de Neoplasias , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Supresoras de Tumor/genética

RESUMEN

PURPOSE: Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth. EXPERIMENTAL DESIGN: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-ras(G12V)/p16sh. In vivo NF-κB activation-dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA. RESULTS: rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014). CONCLUSIONS: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1α-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC.

Asunto(s)

FN-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptores de Interleucina-1/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Comunicación Autocrina , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-1alfa/metabolismo , Masculino , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Receptores de Interleucina-1/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22(-phox) expression via NF-κB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of ß-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redox-mediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment.

Asunto(s)

Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/fisiología , Oxidación-Reducción/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Animales , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Desoxicitidina/farmacología , Glutatión/metabolismo , Humanos , Isotiocianatos/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Interferencia de ARN/fisiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Gemcitabina

RESUMEN

BACKGROUND: Overexpression of integrin ß6 plays an important role in a variety of malignant tumor invasion and metastasis. METHODS: The expression levels of integrin ß6, matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by immunohistochemistry with human follicular thyroid carcinomas. Then we investigated their correlation with clinical outcomes parameters, relationship, and the survival time. RESULTS: The integrin ß6 staining was expressed in cellular membrane and cytoplasm of follicular thyroid carcinoma cells. The MMP-2 and MMP-9 expressions were mainly found in cellular cytoplasm. In correlation with the clinical outcome parameters of 60 patients, there were significant statistical differences of integrin ß6, MMP-2, and MMP-9 expression levels in different size of tumor. Integrin ß6 and MMP-9 expressions have significant statistical differences in T classifications. MMP-2 and MMP-9 expressions have significant statistical differences in different M classification. Other clinical outcome parameters had no significant statistical differences. CONCLUSION: Integrin ß6 expression correlated significantly with MMP-9 expression, and may be a valuable recurrence indicator for follicular thyroid carcinomas.

Asunto(s)

Adenocarcinoma Folicular/metabolismo , Biomarcadores de Tumor/metabolismo , Cadenas beta de Integrinas/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Adenocarcinoma Folicular/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Pronóstico , Adulto Joven

RESUMEN

Activation of K-ras and inactivation of p16 are the most frequently identified genetic alterations in human pancreatic epithelial adenocarcinoma (PDAC). Mouse models engineered with mutant K-ras and deleted p16 recapitulate key pathological features of PDAC. However, a human cell culture transformation model that recapitulates the human pancreatic molecular carcinogenesis is lacking. In this study, we investigated the role of p16 in hTERT-immortalized human pancreatic epithelial nestin-expressing (HPNE) cells expressing mutant K-ras (K-rasG12V). We found that expression of p16 was induced by oncogenic K-ras in these HPNE cells and that silencing of this induced p16 expression resulted in tumorigenic transformation and development of metastatic PDAC in an orthotopic xenograft mouse model. Our results revealed that PI3K/Akt, ERK1/2 pathways and TGFα signaling were activated by K-ras and involved in the malignant transformation of human pancreatic cells. Also, p38/MAPK pathway was involved in p16 up-regulation. Thus, our findings establish an experimental cell-based model for dissecting signaling pathways in the development of human PDAC. This model provides an important tool for studying the molecular basis of PDAC development and gaining insight into signaling mechanisms and potential new therapeutic targets for altered oncogenic signaling pathways in PDAC.

Asunto(s)

Adenocarcinoma/patología , Carcinogénesis/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Regulación hacia Abajo , Genes ras/genética , Neoplasias Pancreáticas/patología , Adenocarcinoma/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Ratones , Mutación , Metástasis de la Neoplasia , Neoplasias Pancreáticas/genética

RESUMEN

Radiofrequency ablation (RFA) is a minimally invasive technique used to treat liver tumors. The current study presents the case of a patient with hepatocellular carcinoma who suffered from post-operative pericardial effusion following RFA treatment. We hypothesize that RFA thermal conduction may damage the diaphragm and pericardium, leading to local edema in the pericardium. RFA is a minimally invasive technique, however, adequate preparatory work must be performed prior to surgery, including a comprehensive assessment of the patient. During surgery, the location and extent of the region to receive RFA must be determined precisely in order to reduce the range of damage and to avoid post-operative complications. This study describes a case of pericardial effusion caused by RFA of liver cancer. We analyzed the causes and preventive measures for pericardial effusion in order to contribute to the prevention pericardial effusion that is complicated by RFA of liver cancer.

RESUMEN

Over-expression of integrin αvß6 and increased numbers of cancer-associated fibroblasts (CAFs) play an important role in the development and progression of cancers. The aim of this study is to investigate the expression level of integrin αvß6 and CAF numbers, their correlation with clinicopathologic features and their role in the prognosis of human gastric cancers. The expression levels of integrin αvß6 and α-SMA in CAFs were analyzed by immunohistochemistry. Their correlation with clinicopathologic features, the relationships and the survival time of patients were also analyzed. The integrin αvß6 expression levels were analyzed mainly in gastric cancers. The α-SMA expression levels were analyzed mainly in gastric cancers and paraneoplastic tissues. Patients with positive integrin ß6 and α-SMA expression have a significantly lower overall survival rate than those with negative integrin ß6 and α-SMA expression (P < 0.05). A multivariate analysis using a log-rank test indicated that patients with positive integrin ß6 and α-SMA expression and/or a diffuse type of gastric cancer had a significantly poorer overall survival rate than did those with negative integrin ß6 expression (P < 0.05). Integrin ß6 expression correlated significantly with CAF numbers and served as a valuable prognostic indicator for human gastric cancers.

Asunto(s)

Antígenos de Neoplasias/genética , Carcinoma/patología , Fibroblastos/patología , Integrinas/genética , Invasividad Neoplásica/patología , Neoplasias Gástricas/patología , Actinas/genética , Adulto , Anciano , Carcinoma/genética , Carcinoma/mortalidad , Progresión de la Enfermedad , Femenino , Fibroblastos/metabolismo , Humanos , Cadenas beta de Integrinas/genética , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Tasa de Supervivencia